The long-term objective of the proposed research is to develop contemporary computer assisted quantitative histologic techniques in an attempt to define better the nature and locus of structural abnormalities in a variety of human neuropsychiatric illnesses, especially schizophrenia and unclassified mental retardation syndromes. Most of these disorders are characterized clinically by abnormalities of cognition and behavior reflecting, at least at some level, disordered function of forebrain cortical structures. Our working hypothesis is that these pronounced abnormalities of cortical function may also be associated with abnormalities in the structure and organization of cortical neurons. Traditionally, neuropathologic analysis in these cases has not disclosed consistent and unequivocal structured changes. It is possible that significant changes are present, but are beyond the resolution of the relatively crude qualitative methods employed to date. We propose to re-examine the structure of individual cortical neurons, as revealed by Golgi impregnations, and the structural organization of cortical neurons, as revealed in general cell strains, using computer assisted quantitative morphologic analyses. Strategies for morphometric analysis of Golgi impregnated neurons will be developed and tested first in the laboratory mouse. Principles derived from analysis of normal neurons will be tested in animal models of neurologic disease to determine the nature and specificity of structured changes in response to a variety of pathologic insults. Results from animal studies will provide the conceptual basis for interpreting changes encountered in Golgi impregnated cortical structures from people with neuropsychiatric disease. If successful, abnormalities identified in this way may provide new insights into the pathophysiology of nerve cell malfunction in these disorders.